Abstract: Regioselective
N-alkylation of 4-chloro-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine
(1)
with ethyl 3-bromopropionate under
liquid-liquid phase-transfer reaction conditions and further
saponification of
the ester function under formation of compound 3b is
described. Subsequent
SNAr
substitution of the 4-chloro
substituent by an amino function and reductive removal of the
2-methylthio
group of 3b
gives, via 4a,
the title compound 4b.

Keywords: 7-Deazaadenine,
Tubercidin,
Functionalization

The
adenine-isosteric
7-deazaadenine represents the heterocyclic nucleobase of the nucleoside
antibiotic tubercidin (1)
[1]. This
base is able to form regular Watson-Crick
but not Hoogsteen
base pairs [2].

Functionalized
derivatives of 7-deazaadenine
such as compound 4b
are of considerable interest because they can be easily coupled to
polymers or surfaces carrying amino functions lending them the
functionality of a particular modified nucleobase [3]. Coupling of
compounds 3b or
4a,b
to amino-functionalized lipids [4] or phospholipids such as kephalines
may lead to potential organo- or hydrogelators. Moreover, compound 4b
represents the 7-deaza analogue of 3-(adenine-9-yl)propanoic acid – a
by-product of the antihypocholesteremic eritadenine isolated from the Shiitake
mushroom Lentinus
edodes Sing [5].Furthermore,
compounds 3b
and 4a,b
can be used for the synthesis of base-modified peptidyl nucleic acids
(PNA) [6].

The
preparation of 4b
started from 4-chloro-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine
(2)
– synthesized in 5 steps according to
the literature [7-10] - which was alkylated with ethyl
3-bromopropionate under
liquid-liquid phase transfer catalysis conditions with
tetrabutylammonium
hydrogensulfate as catalyst to yield compound 3a
[3]. Subsequent saponification of the ester
group gave the acid 3b.
Nucleophilic displacement of the
4-chloro substituent by an amino group using aqueous ammonia (→ 4a)
followed by reductive removal of the
2-SCH3 group with Raney Nickel
gave the title compound 4b;
its
3D-optimized structure is shown in the figure. Studies on the coupling
of 4b
to various carrier molecules is
underway.